Neuron: August 17, 2022 (Volume 110, Issue 16)

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[Functional neuroimaging in psychiatry and the case for failing better](%2F%2Fwww.cell.com%2Fneuron%2Ffulltext%2FS0896-6273(22)00647-X/1/01000182ac7ec92e-4dda382f-1878-4693-ab3f-4711fe891c84-000000/SyUhaK_Uidv1PYpe_S-hY6e14ACRiuUUNaxbolPvyqg=262) Nour et al. [Sodium-calcium exchanger-3 regulates pain "wind-up": From human psychophysics to spinal mechanisms](%2F%2Fwww.cell.com%2Fneuron%2Ffulltext%2FS0896-6273(22)00458-5/1/01000182ac7ec92e-4dda382f-1878-4693-ab3f-4711fe891c84-000000/qupgDacBNtmCwpcO6EAoDZzTwj9CNjv52ScCwewN4nU=262) Trendafilova et al. [Single-cell activity and network properties of dorsal raphe nucleus serotonin neurons during emotionally salient behaviors](%2F%2Fwww.cell.com%2Fneuron%2Ffulltext%2FS0896-6273(22)00456-1/1/01000182ac7ec92e-4dda382f-1878-4693-ab3f-4711fe891c84-000000/NM7AEfW6x1Am1XSmdk3C-5AItxk-rMehhrmySrK1VG4=262) Paquelet et al. Online now --------------------------------------------------------------- [Astrocytic Piezo1-mediated mechanotransduction determines adult neurogenesis and cognitive functions](%2F%2Fwww.cell.com%2Fneuron%2Ffulltext%2FS0896-6273(22)00655-9/1/01000182ac7ec92e-4dda382f-1878-4693-ab3f-4711fe891c84-000000/20LnZpRkEHMiPN0q6LG8QXRrNo-1sphPb_6LJfaCSrg=262) Chi et al. [Task specificity in mouse parietal cortex](%2F%2Fwww.cell.com%2Fneuron%2Ffulltext%2FS0896-6273(22)00662-6/1/01000182ac7ec92e-4dda382f-1878-4693-ab3f-4711fe891c84-000000/6igVtIZz-QLT5tECt47NjvtTPxDSbxc8Re5R_C7kASo=262) Lee et al. [Neuroinflammatory disease disrupts the blood-CNS barrier via crosstalk between proinflammatory and endothelial-to-mesenchymal-transition signaling](%2F%2Fwww.cell.com%2Fneuron%2Ffulltext%2FS0896-6273(22)00660-2/1/01000182ac7ec92e-4dda382f-1878-4693-ab3f-4711fe891c84-000000/95IVAfp9I-aGtN6lshPO1C4eeS4bxzM64gzawPzd6R8=262) Sun et al. [Glial control of sphingolipid levels sculpts diurnal remodeling in a circadian circuit](%2F%2Fwww.cell.com%2Fneuron%2Ffulltext%2FS0896-6273(22)00661-4/1/01000182ac7ec92e-4dda382f-1878-4693-ab3f-4711fe891c84-000000/m87c4m_fOOCVbDhKcOM7YwVoFz2OyW8P9PVUg6wxbLo=262) Vaughen et al. Table of Contents Previews --------------------------------------------------------------- [Protecting against summation of pain](%2F%2Fwww.cell.com%2Fneuron%2Ffulltext%2FS0896-6273(22)00650-X%3Fdgcid=raven_jbs_etoc_email/1/01000182ac7ec92e-4dda382f-1878-4693-ab3f-4711fe891c84-000000/bScW3PJIK71n3pITitEtrZzQfxNMR3LmaMNNYQByX-w=262) Daniela Mauceri, Rohini Kuner Temporal summation in the spinal cord is linked to pathological pain. In a translational genetic association study in this issue of Neuron, Trendafilova et al. (2022) identify the sodium-calcium exchanger 3 as a negative regulator of temporal summation and hypersensitivity via its modulation of calcium homeostasis. [Live, die, or regenerate? New insights from multi-omic analyses](%2F%2Fwww.cell.com%2Fneuron%2Ffulltext%2FS0896-6273(22)00671-7%3Fdgcid=raven_jbs_etoc_email/1/01000182ac7ec92e-4dda382f-1878-4693-ab3f-4711fe891c84-000000/m5knL6IDthb3DjH2nNhhDffTOFY5IaKyXGeJGSEKM3Y=262) Nicole Y. Tsai, Derek S. Welsbie, Xin Duan In this issue of Neuron, three studies establish new strategies for efficient retinal neuroprotection and optic nerve regeneration. Tian et al. (2022) carry out a multi-omics screen and identify key transcriptional regulators of axon injury signaling leading to cell death; Jacobi et al. (2022) and Li et al. (2022) combine retrograde tracing and single-cell RNA-seq (scRNA-seq) to uncover a new molecular roadmap for axon regeneration. [Illuminating complexity in serotonin neurons of the dorsal raphe nucleus](%2F%2Fwww.cell.com%2Fneuron%2Ffulltext%2FS0896-6273(22)00658-4%3Fdgcid=raven_jbs_etoc_email/1/01000182ac7ec92e-4dda382f-1878-4693-ab3f-4711fe891c84-000000/lobzJSZgAnd_XGJS1u8Y0AfnHtIL0PAOuDMgLabIcMc=262) Jalal Baruni, Liqun Luo The function of serotonin in the mammalian brain has been challenging to unravel. In this issue of Neuron, Paquelet et al. (2022) employ microendoscopy to record over 2,000 dorsal raphe serotonin neurons, yielding new insights into their activity from the single neuron to the population level. [Novelty, uncertainty, and the looming horizon](%2F%2Fwww.cell.com%2Fneuron%2Ffulltext%2FS0896-6273(22)00651-1%3Fdgcid=raven_jbs_etoc_email/1/01000182ac7ec92e-4dda382f-1878-4693-ab3f-4711fe891c84-000000/WTovrJkfOIMNTcLPVfnwvodaOaEm6leWrUQhx2kGvP8=262) Cameron D. Hassall, Laurence T. Hunt Novelty and uncertainty are powerful drivers of exploration that are often conflated. In this issue of Neuron, Cockburn and colleagues dissociate the two and report a key interaction: close to task termination, novel options appear much more attractive relative to uncertain options. Perspective --------------------------------------------------------------- [Functional neuroimaging in psychiatry and the case for failing better](%2F%2Fwww.cell.com%2Fneuron%2Ffulltext%2FS0896-6273(22)00647-X%3Fdgcid=raven_jbs_etoc_email/1/01000182ac7ec92e-4dda382f-1878-4693-ab3f-4711fe891c84-000000/VLDKk9qIWhgyX0AB_b14XbLVUNoXWOCbh-NiGdZliSg=262) Matthew M. Nour, Yunzhe Liu, Raymond J. Dolan The confluence of functional neuroimaging and cognitive neuroscience has revolutionized psychiatric research, yet clinical translation has been lacking. Nour et al. provide a critical perspective on this impasse and suggest how the field might fare better in the future. Review --------------------------------------------------------------- [The emergence and influence of internal states](%2F%2Fwww.cell.com%2Fneuron%2Ffulltext%2FS0896-6273(22)00407-X%3Fdgcid=raven_jbs_etoc_email/1/01000182ac7ec92e-4dda382f-1878-4693-ab3f-4711fe891c84-000000/2CLr034gwz-I_ICJlXjV99AgJZAbOAVBYU1-bH0Hjjg=262) Steven W. Flavell, Nadine Gogolla, Matthew Lovett-Barron, Moriel Zelikowsky In this review, Flavell, Gogolla, Lovett-Barron, and Zelikowsky synthesize research across animal models to discuss the classification of internal states, the roles of state-modulating neurons, and the impact of diverse states on neural dynamics and behavior. Articles --------------------------------------------------------------- [Sodium-calcium exchanger-3 regulates pain “wind-up”: From human psychophysics to spinal mechanisms](%2F%2Fwww.cell.com%2Fneuron%2Ffulltext%2FS0896-6273(22)00458-5%3Fdgcid=raven_jbs_etoc_email/1/01000182ac7ec92e-4dda382f-1878-4693-ab3f-4711fe891c84-000000/82OZT6LOVy-FuI8v1zPdBPcaHHczwVfxTRe-ijDXZdA=262) Teodora Trendafilova, Kaustubh Adhikari, Annina B. Schmid, Ryan Patel, Erika Polgár, Kim I. Chisholm, Steven J. Middleton, Kieran Boyle, Allen C. Dickie, Evangelia Semizoglou, Jimena Perez-Sanchez, Andrew M. Bell, Luis Miguel Ramirez-Aristeguieta, Samar Khoury, Aleksandar Ivanov, Hendrik Wildner, Eleanor Ferris, Juan-Camilo Chacón-Duque, Sophie Sokolow, Mohamed A. Saad Boghdady, André Herchuelz, Pierre Faux, Giovanni Poletti, Carla Gallo, Francisco Rothhammer, Gabriel Bedoya, Hanns Ulrich Zeilhofer, Luda Diatchenko, Stephen B. McMahon, Andrew J. Todd, Anthony H. Dickenson, Andres Ruiz-Linares, David L. Bennett Open Access Repetitive noxious stimuli increase pain perception (wind-up). Trendafilova et al. demonstrate significant genetic association between the sodium-calcium exchanger NCX3 and human wind-up. Mice lacking NCX3 show increased pain-related behavior and spinal hyper-excitability due to slowed Ca2+ clearance. Enhanced spinal expression of NCX3 reduced pain in mice, suggesting therapeutic potential. [Presynaptic FMRP and local protein synthesis support structural and functional plasticity of glutamatergic axon terminals](%2F%2Fwww.cell.com%2Fneuron%2Ffulltext%2FS0896-6273(22)00501-3%3Fdgcid=raven_jbs_etoc_email/1/01000182ac7ec92e-4dda382f-1878-4693-ab3f-4711fe891c84-000000/kFY3y8M7gsRqf5yYOSUm1MH9vxV7CkSspT8Di0bYuAo=262) Hannah R. Monday, Shivani C. Kharod, Young J. Yoon, Robert H. Singer, Pablo E. Castillo Monday, Kharod et al. report that neuronal activity regulates presynaptic FMRP function and the local synthesis of β-actin. In vitro activity and in vivo experience engage the FMRP-dependent spatiotemporal regulation of protein synthesis that is required for presynaptic remodeling and long-term changes in neurotransmitter release. [Core transcription programs controlling injury-induced neurodegeneration of retinal ganglion cells](%2F%2Fwww.cell.com%2Fneuron%2Ffulltext%2FS0896-6273(22)00541-4%3Fdgcid=raven_jbs_etoc_email/1/01000182ac7ec92e-4dda382f-1878-4693-ab3f-4711fe891c84-000000/HOsC4IY2_itfqJP03BQmDT4gXeItuBd6tElRuA_a_0A=262) Feng Tian, Yuyan Cheng, Songlin Zhou, Qianbin Wang, Aboozar Monavarfeshani, Kun Gao, Weiqian Jiang, Riki Kawaguchi, Qing Wang, Mingjun Tang, Ryan Donahue, Huyan Meng, Yu Zhang, Anne Jacobi, Wenjun Yan, Jiani Yin, Xinyi Cai, Zhiyun Yang, Shane Hegarty, Joanna Stanicka, Phillip Dmitriev, Daniel Taub, Junjie Zhu, Clifford J. Woolf, Joshua R. Sanes, Daniel H. Geschwind, Zhigang He By independent in vivo genetic screen and multi-omic analysis of injured retinal ganglion cells, Feng et al. identify four transcription factors, which act as complementary critical regulators of neuronal survival following injury. These genes regulate two distinct degenerative programs in response to extrinsic and intrinsic stressors, respectively. [Overlapping transcriptional programs promote survival and axonal regeneration of injured retinal ganglion cells](%2F%2Fwww.cell.com%2Fneuron%2Ffulltext%2FS0896-6273(22)00540-2%3Fdgcid=raven_jbs_etoc_email/1/01000182ac7ec92e-4dda382f-1878-4693-ab3f-4711fe891c84-000000/__WEFjyQfmuNgPppsFKfOVBZemYW2SIw6JhnoGBCdi4=262) Anne Jacobi, Nicholas M. Tran, Wenjun Yan, Inbal Benhar, Feng Tian, Rebecca Schaffer, Zhigang He, Joshua R. Sanes Several interventions promote survival and regeneration of retinal ganglion cells following injury. scRNA-seq analysis shows that these interventions downregulate a gene expression program associated with cell death and upregulate programs associated with survival and regeneration. Overexpression of some regeneration module genes enhances RGC survival and axon regeneration in vivo. [Single-cell transcriptome analysis of regenerating RGCs reveals potent glaucoma neural repair genes](%2F%2Fwww.cell.com%2Fneuron%2Ffulltext%2FS0896-6273(22)00601-8%3Fdgcid=raven_jbs_etoc_email/1/01000182ac7ec92e-4dda382f-1878-4693-ab3f-4711fe891c84-000000/fU6SmxgU_HhtkjcsJTBIxu92EMFvH_MJtclAAD6YOIc=262) Liang Li, Fang Fang, Xue Feng, Pei Zhuang, Haoliang Huang, Pingting Liu, Liang Liu, Adam Z. Xu, Lei S. Qi, Le Cong, Yang Hu Combined retrograde regenerating axon tracing and Smart-Seq2 single-cell sequencing approaches revealed multiple pro-regeneration genes downstream of Pten deletion. Two of these genes, Anxa2 and Mpp1, also presented striking neuroprotection and visual function preservation in a mouse glaucoma model. Additionally, we established the role of tPA-Anxa2-ILK axis in neural repair. [Single-cell activity and network properties of dorsal raphe nucleus serotonin neurons during emotionally salient behaviors](%2F%2Fwww.cell.com%2Fneuron%2Ffulltext%2FS0896-6273(22)00456-1%3Fdgcid=raven_jbs_etoc_email/1/01000182ac7ec92e-4dda382f-1878-4693-ab3f-4711fe891c84-000000/T8Ag5rcRc9gPUaCsGvVIe24mf59A1Wm8hTL23cumkiw=262) Grace E. Paquelet, Kassandra Carrion, Clay O. Lacefield, Pengcheng Zhou, René Hen, Bradley R. Miller Open Access Paquelet et al. use miniaturized microscopy to visualize the activity of serotonergic neurons in the dorsal raphe nucleus of mice during emotional behaviors. Their results show that dorsal raphe serotonin neurons are modulated during emotionally salient behaviors using highly correlated ensembles with mixed selectivity and biases in downstream connectivity. [Neural mechanisms of credit assignment for inferred relationships in a structured world](%2F%2Fwww.cell.com%2Fneuron%2Ffulltext%2FS0896-6273(22)00462-7%3Fdgcid=raven_jbs_etoc_email/1/01000182ac7ec92e-4dda382f-1878-4693-ab3f-4711fe891c84-000000/6Slj5WIZE2sWL87yaRa223t3iBmQONYcp3mrS941_Jk=262) Phillip P. Witkowski, Seongmin A. Park, Erie D. Boorman Witkowski et al. show that prefrontal cortical areas both track the inferred “position” in a task space defined by hierarchically related associations governed by a common latent cause and reinstate these latent causes at feedback to assign credit to the inferred associations. [Novelty and uncertainty regulate the balance between exploration and exploitation through distinct mechanisms in the human brain](%2F%2Fwww.cell.com%2Fneuron%2Ffulltext%2FS0896-6273(22)00502-5%3Fdgcid=raven_jbs_etoc_email/1/01000182ac7ec92e-4dda382f-1878-4693-ab3f-4711fe891c84-000000/GMXAGZg7tL6kk9IAY1Vxq4fE3091K59vgN1xID2x_T8=262) Jeffrey Cockburn, Vincent Man, William A. Cunningham, John P. O’Doherty Cockburn et al. show that novelty and uncertainty are used by the human brain to guide distinct exploration strategies. Uncertainty-directed exploration considers the prospective benefit of new information, whereas novelty motivates exploration by inflating the brain’s expectation of reward, offering a feasible decomposition of an otherwise intractable explore/exploit dilemma. 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